Synthesis procedure for biphenylimidazolyl-(1)-phenylmethane and related compounds

ABSTRACT

Synthesis of Bifonazole by reducing 4-phenylbenzophenone to the alcohol and reacting the alcohol in solid phase under microwave irradiation with imidazole.

BACKGROUND

The instant invention is related to the synthesis of active principlesof medicaments, specifically to the synthesis of antimycotics. Ourmethod of synthesis consists of the manufacture ofbiphenylimidazolyl-(1)-phenylmethane, or(biphenyl-4yl)-imidazol-1-yl-phenylmethane, from 4-phenylbenzophenone(1). The method consists of two synthesis steps: the reduction of (I) tobiphenylphenyl-carbinol (II) and the subsequent addition of imidazole(III) to the alcohol produced. Both synthesis steps are fast and of easyexecution; the whole synthesis process does not exceed three hours.Contrary to previous methods, it does not require the use of thionylchloride, or solvent in the synthesis process. It yields between 70 to74% biphenylimidazolyl-(1)-phenylmethane (IV).

Bifonazole, or (biphenyl-4-yl)-imidazol-1-yl-phenylmethane is a potentantimycotic, prepared for the first time by Bayer in 1974, patentgranted in 1976 (Ger.Pat. 2,461,406). Since then, many modificationshave been made to the same patent, all of which are registered by Bayer(U.S. Pat. No. 4,118,487).

The method of synthesis presented in Ger.Pat. 2,461,406 uses4-phenylbenzophenone as partition reactant, and has 2 or three steps,depending on the variation of synthesis to use. One of the variationscomprises the dissolution of 4-phenylbenzophenone in ethanol, thenadding sodium borohydride in a 1:2 molar relation to 4-phenylbenzophenone, for the reduction of ketone to alcohol. The system isheated to reflux during fifteen hours, it is let to cool down and thereaction mixture is hydrolyzed with water acidulated with HCl, the solidobtained is purified by recrystallization in ethanol. 89% of thetheoretical yield of biphenyl-phenyl-carbinol is obtained.

The second and third stage of synthesis consists of making imidazolereact with thionyl chloride, using acetonitrile as solvent; theoperation is performed at 10° C. To the resulting thionylbisimidazolesolution, biphenylphenyl-carbinol is added in a 1:4 molar relation tothe thionyl. After fifteen hours at room temperature, the solvent isremoved by vacuum distillation. The remaining is dissolved in chloroformand washed with water, the organic phase is dried over sodium sulfate;after filtering, the solvent is vacuum distilled. The resulting solid ispurified by recrystallization in acetonitrile. Bifonazole is obtained in56% yield in relation to the theoretical.

Another variant consists of making biphenylphenylchloromethane react(product chlorated from biphenyl-phenyl-carbinol), withn-trimethylsilylimidazole dissolved in acetonitrile. The system isheated at reflux during fifteen hours, then the solvent is distilled,the residue is purified by recrystallization in ethyl acetate.Bifonazole is obtained in 50% yield in relation to the theoretical.

The German Patent 3,538,873 (1987) describes a method of synthesis forseveral molecules with antimycotic properties, among them Bifonazole;reacting 4-benzoylbiphenyl with imidazole in a 1:4 molar relation inp-CH₃C₆H₄SO₃H; heating the system at 180 degrees Celsius; then addingformic acid dropwise during five hours. A mixture of water-formic acidis distilled at the end of the reaction. Bifonazole is obtained in a72.3% yield in relation to the theoretical.

Other methods use dichloromethane as solvent and add triethylaminemaking react biphenylphenylchloromethane with n-trimethylsilylimidazoleat reflux during 5 to 10 hours; or forming n-trimethylsilylimidazole “insitu” from imidazole and CH₃SiCl (Es. Patent 531,107).

Another preparation starts from cyciocondensation of 4-PhC₆H₄CHPhNH₂,CICH₂CH₂NH₂HCl and HC(OEt)₃ in the presence of a proton acceptor inEtOH, followed by a dehydrogenation of the resulting (biphenylbenzyl)imidazoline, which was dehydrogenated with DDQ in benzene, to yieldBifonazole (Es. Patent 549,793), no yield reported.

Bifonazole has also been prepared by benzoylation of imidazole withPhCOCl, yielding 74.7% of 1-benzoylimidazole which is subject to reactwith Gringnard's reactant 4-PhC₆H₄MgBr followed by a tosylation andsubsequent reduction with sodium cyanoborohydride inhexamethylphosphoramide, to yield 68.2% Bifonazole (Es. Patent 539,345).

One can also start from imidazole, which is make to react with formicacid at 220° C. to obtain the amide; when cooling the system at 50° C.,a mixture of 4-phenylbenzophenone is added in formic acid, and thesystem is heated at 200° C. during twenty hours, then it is stirredovernight with KOH, water and toluene to produce Bifonazole. No yieldreported (East Germany DD 249.268).

SUMMARY OF THE INVENTION

Our method of synthesis for Bifonazole uses 4-phenylbenzophenone as astarting reactant, and it comprises two steps: the first one consists ofthe reduction of ketone to alcohol with sodium borohydride, and thesecond, of the reaction of biphenyl-phenyl-carbinol with imidazole.

The reduction is performed in the presence of alumina, using a smallamount of ethanol or other protic solvent, just enough to form a kind ofpaste with alumina, sodium borohydride and 4-phenylbenzophenone in acontainer adapted to a condenser; the reaction is strongly exothermicand does not need external heating; the reaction lasts from 10 to 60minutes; then the product is hydrolyzed with water acidulated with HCI.The product is separated by filtration. A 99% conversion of (I) to (II)is obtained and 92-96% of (II) after recrystallization starting fromethanol, where the reduction of 4-phenyl-benzophenone is carried out inthe presence of sodium borohydride in the presence of alumina andethanol and the time of reaction is from 10 to 60 minutes, and theconversion of 4-phenyl-benzophenone into biphenyl-phenyl-carbinol is90-99%.

The second step of synthesis is performed through a reaction in solidphase, in excess of imidazole. The mixture is heated in a microwaveoven. The microwave energy used to carry out the solid phase reactioncan be determined through routine experimentation, since it is easy toanalyze for the Bifonazole product, with the exemplification set forthherein as guidelines. Microwave times of 3 to 40 minutes can often beused. For example, for a sample weight of about 0.75 g, the sample canbe placed in a conventional microwave oven rated at 850 watts at about22-25 cm from the Magnetron with the microwave run at 30 to 50% powerfor about 30 minutes. The product is recrystallized from acetonitrile.70 to 74% of the theoretical yield (pure product) is obtained inrelation to the initial amount of 4-phenylbenzophenone. The greatadvantages of this method are:

-   -   1. The use of thionyl chloride is not necessary.    -   2. The only organic solvents used are ethanol and acetonitrile,        and they are used in small amounts.    -   3. The whole synthesis process lasts two hours.    -   4. High yields are obtained in each synthesis step.    -   5. The environment is not contaminated by using reactants such        as thionyl chloride, or solvents such as benzene,        hexamethylphosphoramide, triethylamine, or toluene.

The process of the present invention can be employed for production ofother triphenyl imidazole methane derivatives, especially the secondstep of solid phase reaction under microwave energy, from the knowntriphenylimidazoyl carbinols whether produced by the carbinol-producingstep herein or not.

DESCRIPTION OF DRAWING

FIG. 1 is an infrared of spectrum obtained Biphenylphenylcarbinol underexperimental conditions of Example No. 1.

FIG. 2 is an infrared spectrum of obtained Bifonazole under experimentalconditions of Example No. 1.

FIG. 3 is an infrared spectrum of Bifonazole of Laboratories Chile.

FIG. 4 is a mass spectrum of obtained Bifonazole under experimentalconditions of Example No. 1.

FIG. 5 is a NMR¹H spectrum of obtained Bifonazole under experimentalconditions of Example No. 1.

DETAILED DESCRIPTION

In the practice of this invention, 1 to 0.05 moles of benzophenone canbe reacted with 1.0 mole of borohydride; 0.01 to 25 mass units of thealumina can be used for 1.0 mass unit of the benzophenone; 1 to 2 massunits of the protic solvent can be used for 1.0 mass unit of thebenzophenone; and the molar ratio of carbinol to imidazole can be 1:1-8.The reaction between biphenyl-phenyl carbinol and imidazole can becarried out in the absence of any organic or inorganic solvent.

EXAMPLE 1

First Synthesis step: 10.0 g (3.87×10⁻² mole) of (I), were supported bychemisorbtion in 10.0 g of alumina using 20 mL ethanol until forming apaste (slightly humid), to which 1.5 g of sodium borohydride (3.96×10⁻²mole) is added. The system is stirred by magnetic stirring during fortyminutes at room temperature. This is performed in a container with areflux system. Then acidulated water at pH1 was added to the system tohydrolyze excess of borohydride; the product with the alumina supportwas vacuum filtered in a Buchner; the support loaded with the reactionproduct is washed with water until neutral pH of the filtrate; then theloaded support is washed with ethanol at 70° C. with stirring. 99%conversion of (I) to (II) was obtained. The alumina is filtered and thefiltrate is left to crystallize. 92% of the pure alcohol (II) wasobtained. The products were analyzed by TLC (thin layer chromatography)and infrared spectroscopy See spectrum FT-IR in FIG. 1.

Second step of synthesis: 0.2476 g (9.9×10hu 31 4 mole) of (II) wasmixed with 0.5246 g of (III) (7,96×10³¹ ⁴ mole) in absence of solvent,placed in a sealed container, which was placed in a microwave oven (850watts). The sample was irradiated during thirty minutes at 40 power,getting a reaction yield of 71.6% of (IV), or Bifonazole. Mass and MNR′Hspectra of the recrystallized product (see FIG. 4 and 5) were obtained.The infrared spectrum of the product (FIG. 2) can be compared with aknown (registered) IR (FIG. 3).

EXAMPLE 2

First step of synthesis: 93.2% of compound (II) was obtained accordingto the first step of synthesis of Example 1.

Second step of synthesis: 0.25 g (9.6×10⁻⁴ mole) of (II) was mixed with0.5251 g, (7.7×10⁻³ mole) of (III) in absence of solvent, placed in asealed container, which was placed in a microwave oven (850 w). It wasirradiated during thirty minutes at 50 power. Reaction yield afterrecrystallization of the product was 72% of (IV).

EXAMPLE 3

First synthesis step: 96.3% of compound (II) was obtained according tothe first step of synthesis of Example 1.

Second step of synthesis: 0.25 g, (9.6×10⁻⁴mole) of (II) was mixed with0.525 g, (7.7×10⁻³ mole) of (III) in the absence of solvent, placed in asealed container, which was placed in a microwave oven (850 W). It wasirradiated during thirty minutes at 40 power. After recrystallization ofthe product the yield obtained was 73.9% of (IV).

Variations of the invention will be apparent to the skilled artisan.

1. A synthesis procedure for the manufacture ofbiphenylimidazolyl-(1)-phenylmethane, comprising the reduction of4-phenyl-benzophenone and subsequent reaction ofbiphenyl-phenyl-carbinol with imidazole.
 2. A synthesis procedureaccording to claim 1, where the reduction of 4-phenyl-benzophenone iscarried out with sodium borohydride in the presence of alumina.
 3. Asynthesis procedure according to claim 1 claim 2, where the molar ratiobetween 4-phenyl-benzophenone and sodium borohydride is 1:0.5 1-0.05moles of the 4-phenyl-benzophenone to 1.0 mole sodium borohydride(1:0.5-1) .
 4. A synthesis procedure according to claim 1 claim 2, wherethe ratio in mass between alumina and 4-phenyl-benzophenone is 0.01:25-10.01-25:1.
 5. A synthesis procedure according to claim 1, where a proticsolvent is used, for example ethanol .
 6. A synthesis procedureaccording to claim 1 claim 5, where the protic solvent used is in a massratio with 4-phenyl-benzophenone of 1:2-1 1-2:1.
 7. A synthesisprocedure according to claim 1 claim 2, wherein ethanol is used as aprotic solvent in the synthesis procedure and where the time of reactionbetween sodium borohydride and 4-phenyl-benzophenone in the presence ofalumina and ethanol is from 10 to 60 minutes.
 8. A synthesis procedureaccording to claim 7, where no heating is necessary besides theexothermal effect produced by the reaction itself.
 9. A synthesisprocedure according to claim 8, where the conversion of4-phenyl-benzophenone into biphenyl-phenyl-carbinol is 90-99%.
 10. Thesynthesis procedure according to claim 1, where thebiphenyl-phenyl-carbinol reacts in a further step of synthesis withimidazole, in a molar ratio of biphenyl-phenyl-carbinol to imidazole of1-1:8 1:1-8.
 11. A synthesis procedure according to claim 10, where thereaction between biphenyl-phenyl-carbinol and imidazole is carried outin the absence of any organic or inorganic solvent.
 12. A synthesisprocedure according to claim 11, where the reaction betweenbiphenyl-phenyl-carbinol and imidazole is carried out by subjecting thesystem to microwave irradiation.
 13. A synthesis procedure according toclaim 12, where the reaction time is from 3 to 40 minutes.
 14. Asynthesis procedure according to claim 13, wherebiphenylimidazolyl-(1)-phenylmethane is obtained as a reaction productin a yield of 70 to 74% of pure product.
 15. A synthesis procedure forthe manufacture of biphenylimidazolyl-(1)phenylmethane starting from4-phenyl-benzophenone, which consists of two synthesis steps, being thefirst one the reduction of 4-phenyl-benzophenone tobiphenyl-phenyl-carbinol with sodium borohydride in the presence ofalumina, and the second step consists of the reaction betweenbiphenyl-phenyl-carbinol and imidazole assisted by microwaves, and inthe absence of every kind of organic and inorganic solvents, obtaining ayield between 70 to 74% of pure product in a total reaction time of nomore than three hours, starting from 4-phenyl-benzophone.
 16. Thesynthesis procedure according to claim 5, wherein the protic solvent isethanol.